JP3507435B2 - Cyclohexanediol derivative - Google Patents

Description

Detailed Description of the Invention

The present invention provides the formula I

[0002]

[Chemical 4]

Where X is C = CH ₂ or CH ₂ , Y and Z are independently of each other hydrogen, fluorine or hydroxy, and A is --C.ident.C--, --CH =. CH
- or -CH ₂ -CH ₂ - is, R ¹ and R ² are, independently of one another, alkyl or perfluoroalkyl, R ³ relates to novel retiferol derivative is lower alkyl).

The compounds of formula I treat hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, keratokeratosis and keratosis; neoplastic diseases; sebaceous disorders such as acne and seborrheic dermatitis. Or it can be used to prevent.
The compounds of formula I can also be used for reversing the symptoms associated with photodamage, in particular for the oral or topical treatment of skin damaged by sunlight exposure, the effects of wrinkles, elastic fibrosis and premature aging.

The present invention further provides a process for the preparation of compounds of formula I, pharmaceutical compositions containing such compounds and the use of these compounds for the treatment and prevention of the above disorders, as well as the treatment and prevention of the above disorders. For the use of those compounds for the manufacture of a pharmaceutical composition for.

As used herein, "alkyl" is a straight or branched chain alkyl residue containing 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-. Butyl, pentyl,
Amyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.

As used herein, "lower alkyl" refers to a straight or branched chain alkyl residue containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -Butyl, pentyl, amyl and 3-pentyl.

"Perfluorinated alkyl" means an alkyl group as defined above in which a hydrogen atom is replaced by fluorine,
For example, trifluoromethyl, pentafluoroethyl,
Refers to perfluoropropyl and the like.

In the structural formulas presented herein, the bond indicated by the broken line indicates that the substituent is below the plane of the paper, and the bond indicated by the wedge indicates that the substituent is above the plane of the paper. Show.

Preferred compounds of formula I are those in which at least one of Y and Z is hydroxy, and in particularly preferred compounds Y and Z are hydroxy.

Particularly preferred compounds of formula I are those wherein A is -C =
A compound that is C-, for example, (1R, 3R) -5-
[(2E, 9Z) -12,12,12-trifluoro-
11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene) -cyclohexane-1,3-diol, (Z)-(1R, 3S)
-4-methylene-5-[(2E, 9Z) -12,12,
12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene] -cyclohexane-1,3-diol,
(Z)-(1R, 3S) -5-((2E, 9E) -1
2,12,12-Trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-
2,9-Dienylidene) -4-methylene-cyclohexane-1,3-diol, (1R, 3R) -5-[(2
E, 9E) -12,12,12-trifluoro-11-
Trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-2,9-dienylidene] -cyclohexane-1,3-diol, (1R, 3R) -5-[(2
E, 9E) -11-Hydroxy-7,7,11-trimethyl-dodeca-2,9-diene-ylidene] -cyclohexane-1,3-diol, (Z)-(S) -3-
[(2E, 9E) -11-Hydroxy-7,7,11-
Trimethyl-dodeca-2,9-diene-ylidene] -4
-Methylene-cyclohexan-1-ol, (1R, 3
R) -5-[(2E, 9E) -12,12,12-trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-2,9-dienylidene] -cyclohexane-1, It is a 3-diol.

Particularly preferred are compounds of formula I in which A represents a double bond —CH═CH— in the cis configuration.

In a further preferred embodiment, A is --CH ₂
-CH ₂ - compounds of formula I are, for example, (1R, 3
R) -5-[(2E) -12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2-enylidene) -cyclohexane-1,3-diol, (Z)-(1R, 3S)-
5-[(2E) -12,12,12-trifluoro-1
1-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2-enylidene] -4-methylene-
Cyclohexane-1,3-diol, (Z)-(1S)
-3-[(2E) -11-hydroxy-7,7,11-
Trimethyl-dodeca-2-en-ylidene] -4-methylene-cyclohexan-1-ol, (Z)-(1R,
3S) -5-[(E) -11-hydroxy-7,7,1
1-trimethyl-dodeca-2-anylidene] -4-methylene-cyclohexane-1,3-diol, (2E)-
(1R, 3R) -5- (11-hydroxy-7,7,1
1-trimethyl-dodeca-2-anylidene) -cyclohexane-1,3-diol.

Another preferred embodiment is that A is --C.ident.C--.
A compound of formula I which is, for example, (E)-(1R, 3
R) -5- [12,12,12-trifluoro-11-
Hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2-ene-9-ynylidene] -cyclohexane-1,3-diol, (Z)-(1R, 3S)-
4-Methylene-5-[(E) -12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11
-Trifluoromethyl-dodeca-2-ene-9-ylidene] -cyclohexane-1,3-diol, (Z)-
(S) -4-methylene-3-[(E) -12,12,1
2-Trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2-ene-9
-Inylidene] -cyclohexan-1-ol, (10
E, 12Z)-(S) -12- (5-hydroxy-2-
Methylene-cyclohexylidene) -6,6-dimethyl-
2-Methyl-dodeca-10-en-3-yn-2-ol, (10E)-(3R, 5R) -12- (3,5-dihydroxy-cyclohexylidene) -6,6-dimethyl-2- Methyl-dodeca-10-en-3-yn-2-ol.

The compound of formula I has the formula II

[0016]

[Chemical 5]

Wherein Y ', Z'are protected hydroxy groups and R ⁴ is a hydroxy protecting group. A preferred hydroxy protecting group is tert-butyldimethyl for hydroxy groups Y and Z. -Silyl (TBDMS), R ⁴ is preferably trimethylsilyl [Si (C
H ₃ ) ₃ ]) can be obtained by cleavage of the silyl protecting group contained in the compound.

Cleavage of the hydroxy protecting group can be accomplished with an inert solvent,
It can be carried out, for example, with tetrabutylammonium fluoride (TBAF) in tetrahydrofuran.

Intermediate II, which is novel and as such is a further object of the present invention, is represented by Reaction Scheme 1
According to Wittig reaction with a compound of formula III. The compound of formula III is E
It can be prepared according to the method described in P-A0771789.

[0020]

[Chemical 6]

In the formula, the symbols are as defined above.

Compounds of formula (1) that are oxidized to aldehydes (2) can be prepared according to reaction scheme 2.

[0023]

[Chemical 7]

Wherein R ⁵ represents a hydroxy protecting group, preferably a tert-butyldimethylsilyl group, R ⁶ represents another hydroxy protecting group, preferably a tetrahydropyranyl group, R ¹ , R ² and R ³ is as defined above.

Starting from the known 4,4-dialkyl-tetrahydropyran-2-ones, the corresponding 4,4-alkyl-tetrahydropyran-2-ols (3) are obtained by reduction. The alcohol (3) is then reacted with ethoxycarbomethylene-trifosporane to give the corresponding 7-
A hydroxy-hept-2-enoic acid ester (4) is obtained. After protection of the hydroxy group to give the unsaturated ester (5), the double bond is catalytically hydrogenated and then the ester group is reduced to form the corresponding mono-protected diol (6). Protection and deprotection of each hydroxy group yields a mono-protected diol (7), which is a known oxidant,
For example, oxidize to aldehyde (8) with 4-methyl-morpholine-4-oxide and tetrapropylammonium perruthenate. This aldehyde is then first reacted with tetrabromomethane in the presence of 2 equivalents of triphenylphosphine to form (9), then butyllithium and the corresponding ketone derivative (eg R
^In the case of preparing a compound of formula I in which ¹ and R ² are trifluoromethyl, a compound of formula (1a) is obtained after reaction with hexafluoroacetone) for the final deprotection of the primary alcohol, That is, the compound of the formula (1) in which A is —C≡C— is obtained. To obtain the corresponding compound (1b), ie, the compound in which A represents —CH═CH— and the corresponding compound (1c), ie, the compound in which A represents —CH ₂ —CH ₂ —, a further reduction step is required. .

Compounds of formula II can also be prepared by an alternative route shown in Scheme 3.

[0027]

[Chemical 8]

In the formula, the symbols are as defined above.

The pharmacological properties of the compounds of formula I can be determined by the following test procedure.

1. Calcium Liability (Tolerance Test in Mice) This test gives an overview of calcemia liability. Profound changes in calcium homeostasis strongly influence the weight gain of experimental animals. This parameter was used as the primary test for tolerance. Mouse (weight 25-30
g), the vitamin D derivative was subcutaneously administered daily for 4 consecutive days. Body weights were recorded immediately before and at the end of the 5 day treatment period. "Highest tolerated dose" in mice (HTD
_sc ) is the dose that results in zero weight gain during this treatment period.

The following Formula I compounds were tested. A (1R, 3R) -5-[(2E, 9Z) -12,1
2,12-trifluoro-11-hydroxy-7,7-
Dimethyl-11-trifluoromethyl-dodeca-2,9
-Dienylidene) -cyclohexane-1,3-diol, B (Z)-(1R, 3S) -4-methylene-5-
[(2E, 9Z) -12,12,12-trifluoro-
11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene] -cyclohexane-1,3-diol, C (Z)-(1R, 3S) -5-((2E, 9E)-
12,12,12-Trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-11-
Dodeca-2,9-dienylidene) -4-methylene-cyclohexane-1,3-diol, D (1R, 3R) -5-[(2E, 9E) -12,1
2,12-trifluoro-11-trifluoromethyl-
11-hydroxy-7,7-dimethyl-dodeca-2,9
-Dienylidene] -cyclohexane-1,3-diol, E (1R, 3R) -5-[(2E) -12,12,1
2-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2-enylidene) -cyclohexane-1,3-diol, F (Z)-(1R, 3S) -5- [ (2E) -12,
12,12-trifluoro-11-hydroxy-7,7
-Dimethyl-11-trifluoromethyl-dodeca-2-
Anylidene] -4-methylene-cyclohexane-1,3
-Diol, G (Z)-(1R, 3S) -5-[(E) -11-hydroxy-7,7,11-trimethyl-dodeca-2-enylidene] -4-methylene-cyclohexane-1,3-
Diol, H (2E)-(1R, 3R) -5- (11-hydroxy-7,7,11-trimethyl-dodeca-2-enylidene) -cyclohexane-1,3-diol, I (E)-(1R , 3R) -5- [12, 12, 12
-Trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodec-2-ene-9-
Inylidene] -cyclohexane-1,3-diol, J (Z)-(1R, 3S) -4-methylene-5-
[(E) -12,12,12-Trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2-en-9-ynylidene] -cyclohexane-1,3-diol, K (10E)-(3R, 5R) -12- (3,5-Dihydroxy-cyclohexylidene) -6,6-dimethyl-2-methyl-dodeca-10-en-3-yn-2-ol

The results are summarized in Table I below. In the case of calcitriol, an HTD of 0.5 μg / kg was observed. In comparison, in the case of compounds of formula I (compounds AK),
HTD values in the range of 80 to> 5000 μg / kg were observed.

2. A transcription activation assay was used to measure activation of the vitamin D receptor (VDR) by vitamin D analogs in VDR activated cells. For COS cells, human VDR (pSG
5) and three response elements (VDRE3) from the rat osteocalcin gene, thymidine kinase basal promoter and luciferase reporter gene, respectively.
Was co-transfected with the reporter gene containing

From Table I, the compounds AK listed are VDR
It can be seen that it is very powerful in terms of activation. Moreover, all these compounds AK
It has a larger therapeutic range than calcitriol (indicated by the TI shift of calcitriol).

[0035]

[Table 1]

3. Mouse model Orally administered vitamin D analogs can cause epidermal thickening in hairless mice. This skin effect is believed to indicate the anti-psoriatic potential of vitamin D analogs.
The analogs were tested at different doses for 4 days in order to detect compounds exhibiting this epidermal effect at sub-toxic and non-toxic doses (dose that caused only or little weight loss). At the highest tolerated dose, calcitriol itself was not able to manifest skin effects. Calcitriol data are from experimental animals treated for 3 days.

Hairless mice (Moro hr / hr) were treated with test compound in peanut oil for 4 days using 2 to 5 different doses (3 fold increase, 2 per dose group). Feeded daily by feeding. Weigh yourself every day,
Toxicity (calcemia liability) was determined to determine the non-toxic dose level, defined as the dose tolerated without weight loss. On day 5, mice were killed and skin biopsy material was harvested, fixed in formalin and processed for histological evaluation.

The results in Table II below show that many of the reticiferols of formula I are far superior to calcitriol because of the better ratio of effective dose to maximum tolerated dose (HTD _po ). Indicates that. This may imply a greater separation between the desired skin effect (ED ₅₀ ) and the toxic calcemia effect.

[0039]

[Table 2]

4. Pig model Orally administered vitamin D analogs can cause epidermal proliferation in minipigs. This skin effect is believed to indicate the anti-psoriatic potential of vitamin D analogs. The compounds were tested at different doses for 7 days in order to detect compounds showing a cutaneous effect at non-calcemic doses (no calcemia effect). Pigs were observed daily for side effects such as behavior, mobility, bowel movements. On day 7, pigs treated with bromodeoxyuridine (4 mg / kg) were injected intravenously and 2 hours later, skin biopsies (6 mm diameter) and blood were taken for analysis. Skin biopsies were fixed in formalin and paraffin sections prepared using standard techniques. Using standard immunohistochemical techniques, S
Cells in the phase (DNA synthesis phase) were labeled by the binding of a monoclonal antibody specific for the thymidine analog bromodeoxyuridine. The number of labeled epidermal cells per unit length along the surface was recorded as a measure of epidermal proliferation activity (Labeling Index LI). Clinical chemistry was performed using Cobas Mira. Calcitriol itself did not induce hyperproliferation, even at highly toxic doses (9 times the doses that induce hypercalcemia).

[0041]

[Table 3]

No deleterious effects of the compound of formula I were found in effective amounts.

The compounds of formula I require such treatment for the treatment or prevention of hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, keratinization disorders and keratosis or for the treatment of neoplastic diseases. It can be administered orally to warm-blooded animals. More specifically, the above-mentioned compound of the present invention can be orally administered to an adult at a dose of about 50 μg to 500 mg per day for the treatment of the above-mentioned diseases.

The compounds of formula I can be administered topically to warm-blooded animals in need of such treatment for the treatment or prevention of hyperproliferative skin diseases such as psoriasis. More specifically, these compounds are used in an amount of about 50 μg to 500 m / g of topical preparation per day for the treatment of the above diseases.
It can be administered locally in a dosage range of g.

The compounds of formula I can also be administered orally or topically to reverse the symptoms associated with photoinjury.

The dose of the compound of formula I depends on the disease to be treated,
It may vary within wide limits depending on the age and individual symptoms of the patient and on the mode of administration, and will, of course, be fitted to the individual requirements in each particular case.

Oral dosage forms containing a compound of formula I can be included in capsules, tablets and the like with a pharmaceutically acceptable carrier material. Examples of such carrier materials which may be included in capsules and the like include emulsifiers such as polyethylene glycol, solubilizers such as short chain triglycerides such as Miglyol, binders such as tragacanth gum, acacia, corn starch or gelatin, excipients. Agents such as dicalcium phosphate, disintegrants such as corn starch, potato starch or alginic acid, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, wintergreen oil or cherries. Is. Various other materials may be included as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets
It can be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange aroma.

Topical dosage forms containing a compound of formula I are oleaginous,
Includes ointments and creams containing formulations with absorbable, water soluble and emulsion type bases such as petrolatum, lanolin, polyethylene glycols and the like. Lotions are liquids, which range from simple solutions to aqueous or hydroalcoholic preparations containing fines. Lotions may contain suspending agents or dispersing agents such as cellulose derivatives such as ethyl cellulose, methyl cellulose and the like; gelatin or gums containing the active ingredient in an excipient made of water, alcohol, glycerin and the like. Gels are semi-solid preparations made by gelling a solution or suspension of an active ingredient in a carrier vehicle. Excipients, which may be hydrous or anhydrous, are gelled using gelling agents such as carboxypolymethylene and suitable gels using alkali such as sodium hydroxide and amines such as polyethylene cocoamine. The consistency is neutralized.

As used herein, "topical" refers to the use of the active ingredient in a suitable pharmaceutical carrier and applied at the site of injury to exert a local effect. Thus, topical compositions include pharmaceutical dosage forms in which a compound of formula I is externally applied by direct contact with the skin. Topical dosage forms include gels, creams, lotions, ointments, powders, aerosols and other conventional means for applying the drug to the skin, obtained by admixing compounds of formula I with known pharmaceutical topical carrier substances. Including the form of.

The following pharmaceutical composition can be prepared by a method known per se.

[0051] Example A Soft gelatin capsule mg / capsule Active compound 50 Butylated hydroxytoluene (BHT) 0.016 Butylated hydroxyanisole (BHA) 0.016 Fractionated Coconut Oil (Neobee M-5) Or Miglyol 812 Sufficient 160.0

Example B Soft gelatin capsule mg / capsule active compound 50 α tocopherol 0.016 812
Sufficient amount 160.0

Example C Topical Cream mg / g Active Compound 20 Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 60 (Sorbitan Monostearate) 2.0 165 (Glyceryl Monostearate and 4.0 Polyoxyethylene Glycol Stearate) Blend) 60 (Polysorbate 60) 1.0 Mineral oil 4.0 Propylene glycol 5.0 Propylparaben 0.05 BHA 0.05 Sorbitol solution 2.0 Disodium edetate 0.01 Methylparaben 0.18 Distilled water Sufficient amount

[0054] Example D Topical ointment mg / g Active compound 20 Propylene glycol Add to 1g total

Example 1A: (1R, 3R) -5-[(2E, 9Z) -12,1
2,12-trifluoro-11-hydroxy-7,7-
Dimethyl-11-trifluoromethyl-dodeca-2,9
Preparation of -dienylidene) -cyclohexane-1,3-diol a] 4,4-Dimethyl-tetrahydro-pyran-2-ol 4,4-dimethyl-tetrahydro-pyran-2-one 6.05 g (47.2 mmol) It was dissolved in 125 ml of anhydrous tetrahydrofuran and cooled to -78 ° C. Temperature -72
53.1 ml of diisobutylaluminium hydride (1.2M, toluene) were added slowly, keeping below sub-degree. After 90 minutes, GC analysis showed 97% product. -7
1.18 ml of methanol was added at 8 degrees, followed by 2N HC
The excess reagent was destroyed by adding 76 ml of l. Extraction twice with ether, washing with NaCl, drying over sodium sulphate and evaporation of the solvent left a crude product which was subjected to flash chromatography (Si.
Purification with O ₂ , pentane / methyl acetate = 7/3) gave 5.57 g of the title compound as a colorless oil (GC 99% purity).

B] 7-hydroxy-5,5-dimethyl-
Hept-2-enoic acid ethyl ester 4,4-dimethyl-tetrahydro-pyran-2-ol 5.57 g (42.8 mmol) and ethoxycarbonylmethylene-triphenylphosphorane 26.3 g (1.7
6 eq) in 277 ml CH ₃ CN under argon
Heated together for 24 hours. After reducing the volume to about 50 ml, the remaining solution was poured into crushed ice / NH ₄ Cl, extracted twice with ether, dried over sodium sulphate and freed from the solvent. Flash chromatography (Si
O _2, hexane / ethyl acetate = 7/3) to give the heading compound 7.42g as a yellowish oil (E
/ Z about 86/14).

NMR: (major isomer, 1H, δ, TMS) 0.96 (s,
6H), 1.29 (t, 3H), 1.55 (t, 2H), 2.13 (dd, 2H), 3.
72 (t, 2H), 4.19 (q, 2H), 5.82 (dt, 1H), 6.98 (dt,
1H), 1.6 (br, OH).

C] 7- (tert-Butyl-dimethyl-silanyloxy) -5,5-dimethyl-hept-2-enoic acid ethyl ester 7-hydroxy-5,5-dimethyl-hept-2-enoic acid ethyl ester 7 0.42 g (37.05 mmol) is dissolved in 18 ml anhydrous N, N-dimethylformamide and at 0 ° C. with 7.56 g (3 equivalents) of imidazole and 8.38 g (1.5 equivalents) of tert-butyl-dimethyl-chlorosilane. Processed. After keeping the reaction mixture at room temperature overnight, it was poured into crushed ice, extracted twice with ether, washed with water, dried over sodium sulfate and evaporated to dryness. By flash chromatography (SiO ₂ , hexane / ethyl acetate = 97/3), the title compound was 9.94 g.
Was obtained as a colorless oil (also as an E / Z mixture).

D] 7- (tert-Butyl-dimethyl-silanyloxy) -5,5-dimethyl-heptanoic acid ethyl ester 7- (tert-butyl-dimethyl-silanyloxy) -5,5-dimethyl dissolved in 315 ml of ethyl acetate. -Hept-2-enoic acid ethyl ester 9.94 g (31.6 mmo
l) at room temperature and atmospheric pressure for 100 minutes, Pd / C (5
%) 2.6 g. The reaction mixture was filtered through a pad of Celite and the solvent was removed, leaving 9.95 g of the title compound (97.5% pure by GC).

NMR: (1H, δ, TMS) 0.04 (s, 6H), 0.87
(s, 6H), 0.88 (s, 9H), 1.20 (m, 2H), 1.25 (t, 3H),
1.46 (t, 2H), 1.55 (m, 2H), 2.25 (t, 2H), 3.64
(t, 2H), 4.12 (q, 2H).

E] 7- (tert-Butyl-dimethyl-silanyloxy) -5,5-dimethyl-heptane-1-ol 7- (tert-butyl-dimethyl-silanyloxy)-
5,5-Dimethyl-heptanoic acid ethyl ester 9.95
g (31.4 mmol) of anhydrous tetrahydrofuran 125 ml
, And cooled to -10 degrees. Diisobutylaluminium hydride (1.2
65.5 ml of M, toluene) was slowly added. After 25 minutes, the reaction mixture was quenched with water, extracted twice with ether,
Both layers were filtered through a pad of Celite (to remove Al salts), the ethereal solution was washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 8 /
2) gave 8.23 g of the title compound as a slightly yellow oil (purity> 99% by GC).

NMR: (1H, δ, TMS) 0.05 (s, 6H), 0.87
(s, 6H), 0.89 (s, 9H), 1.15-1.6 (m, 8H + OH), 3.65 (2
xt, 2x2H).

F] tert-butyl- [3,3-dimethyl-
7- (Tetrahydro-pyran-2-yloxy) -heptyloxy] -dimethyl-silane 7- (tert-butyl-dimethyl-silanyloxy)-
5,5-Dimethyl-heptane-1-ol 8.23 g
(30.0 mmol) was dissolved in 58 ml of CH ₂ Cl ₂ to give 3,4
-Dihydro-2H-pyran 4.75 ml (1.75 eq)
And pyridinium- (toluene-4-sulfonate)
Treated with 751 mg (0.1 eq). After 60 minutes at ambient temperature the reaction mixture was poured onto crushed ice / Na ₂ CO ₃ , extracted twice with ether, washed with brine, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 97 /
According to 3), 10.17 g of the captioned compound was obtained as a colorless oily substance.

NMR: (1H, δ, TMS) 0.05 (s, 6H), 0.87
(s, 6H), 0.89 (s, 9H), 1.15-1.9 (m, 14H), 3.37 (dt,
1H), 3.50 (m, 1H), 3.64 (t, 2H), 3.75 (dt, 1H),
3.88 (m, 1H), 4.58 (m, 1H).

G] 3,3-Dimethyl-7- (tetrahydro-pyran-2-yloxy) -heptane-1-ol-butyl- [3,3-dimethyl-7- (tetrahydro-
10.17 g (28.4 mmol) of pyran-2-yloxy) -heptyloxy] -dimethyl-silane was treated with 3 equivalents of dry tetrabutylammonium fluoride trihydrate (0.3M in tetrahydrofuran). After 90 minutes at room temperature, the mixture was poured into crushed ice / ether. After normal treatment, flash chromatography (SiO 2
₂ , hexane / ethyl acetate = 7/3) to give 6.28 g of the captioned compound as a colorless oil.

H] 3,3-Dimethyl-7- (tetrahydro-pyran-2-yloxy) -heptanal 8.30 g (61 mmol) of 4-methyl-morpholine-4-oxide.H ₂ O in 160 ml of CH ₂ Cl ₂ and Tetrapropylammonium-perruthenate 574 mg (1.6
3 mmol) to 46 g of molecular sieve (4Å, finely ground)
It was dried by stirring through the flask at room temperature for 2 hours. Next, 3,3-dimethyl-7 was dissolved in CH ₂ Cl ₂ 80ml (tetrahydro - pyran-2-yloxy) -
4.00 g of heptan-1-ol was added within 90 minutes. Filter through a pad of Celite to remove solvent,
Flash chromatography (SiO ₂ , hexane /
Ethyl acetate = 9/1) to give the title compound 2.8.
2 g were obtained as colorless oil (purity> 99 by GC)
%).

NMR: (1H, δ, TMS) 1.05 (s, 6H), 1.3-1.
95 (m, 12H), 2.26 (d, 2H), 3.39 (dt, 1H), 3.50 (m,
1H), 3.75 (dt, 1H), 3.87 (m, 1H), 4.58 (m, 1H),
9.84 (t, 1H).

I] 2- (8,8-dibromo-5,5-dimethyl-oct-7-enyloxy) -tetrahydro-
Pyran CH ₂ Cl _{2 in} 113 ml CBr ₄ 7.48 g (22.6 mmo
l) at -18 degrees, triphenylphosphine 11.8
Reacted with 3 g (45.1 mmol). 5 minutes later, CH ₂ Cl
It was dissolved in ₂ 21 ml 3,3-Dimethyl-7- (tetrahydro - pyran-2-yloxy) - heptanal 2.8
2 g was added dropwise. After 45 minutes, the reaction mixture was diluted with hexane and washed twice with ethanol / H ₂ O = 8/2 to remove triphenylphosphine oxide, the hexane layer was dried over sodium sulfate and evaporated to dryness. . By flash chromatography (SiO ₂ , hexane / ethyl acetate = 9/1), the title compound was 4.554 g.
Was obtained as a colorless oil.

NMR: (1H, δ, TMS) 0.90 (s, 6H), 1.2-1.
9 (m, 12H), 2.01 (d, 2H), 3.39 (dt, 1H), 3.49 (m,
1H), 3.75 (dt, 1H), 3.87 (m, 1H), 4.58 (m, 1H), 6.
41 (t, 1H).

J] 1,1,1-Trifluoro-2-trifluoromethyl-6,6-dimethyl-10- (tetrahydro-pyran-2-yloxy) -dec-3-yne-2
-All 2- (8,8-dibromo-5,5-dimethyl-oct-
7-enyloxy) -tetrahydro-pyran 4.554
g (11.44 mmol) 50 ml anhydrous tetrahydrofuran
And n-butyllithium (1.55
M, hexane, 3 eq.) 22.14 ml. Thirty
After a minute, a large excess of hexafluoro-acetone was introduced into the reaction flask and reacted for 1/2 hour. Poured into crushed ice, extracted twice with ether, washed with brine, dried over sodium sulphate and solvent evaporated to leave a crude product which was flash chromatographed (Si.
Purification with O ₂ , hexane / ethyl acetate = 85/15) gave 5.60 g of the title compound as a colorless oil.

K] 10,10,10-trifluoro-9
-Trifluoromethyl-5,5-dimethyl-dec-7-
In-1,9-diol 1,1,1-trifluoro-2-trifluoromethyl-
6,6-Dimethyl-10- (tetrahydro-pyran-2
-Yloxy) -dec-3-yn-2-ol 3.00
g (6.1 mmol) was dissolved in 40 ml of methanol to give 231 mg of pyridinium- (toluene-4-sulfonate).
It was treated with (0.919 mmol) and kept at room temperature overnight.
The reaction mixture was then poured into crushed ice / Na ₂ CO ₃ , extracted twice with ether, washed with brine, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 7 /
According to 3), 1.736 g of the title compound was obtained as a yellowish oil.

L] (Z) -10,10,10-trifluoro-9-trifluoromethyl-5,5-dimethyl-dec-7-ene-1,9-diol 10,10,10 in 10 ml ethyl acetate. -Trifluoro-
9-trifluoromethyl-5,5-dimethyl-deca-7
-In-1,9-diol 588 mg (1.84 mmol)
At room temperature and atmospheric pressure for 100 minutes at Pd / C (10
%) 100 mg hydrogenated. The reaction mixture was filtered through a pad of Celite and the solvent was removed, leaving 559 mg of the title compound. This was directly used in the next step.

NMR: (1H, δ, TMS) 0.93 (s, 6H), 1.2-1.
4 (m, 6H + 1OH), 2.39 (d, 2H), 3.67 (t, 2H), 4.15 (br
s, 1OH), 5.52 (br d, 1H), 6.09 (dt, 1H) .MS: (M + NH
₄ ) ⁺ 340.

M] (Z) -10,10,10-trifluoro-9-trifluoromethyl-9-hydroxy-5,
5-Dimethyl-dec-7-enal (Z) -10,10,10-trifluoro-9-trifluoromethyl-5,5-dimethyl-dec-7-ene-
It was oxidized by dichromate 2.45 g (3.8 eq) and allowed overnight reaction - 1,9 diol 555mg (1.722mmol), at room temperature, CH ₂ Cl ₂ 54ml pyridinium. Filter through a pad of Celite to remove solvent and flash chromatography (Si
O ₂ , pentane / AcOMe = 8/2) was carried out to give 425 mg of the title compound as a colorless oil.

NMR: (1H, δ, TMS) 0.93 (s, 6H), 1.20
(m, 2H), 1.60 (m, 2H), 2.42 (br d, 2H), 2.44 (t, 2
H), 3.71 (s, OH), 5.53 (br d, 1H), 6.09 (dt, 1H),
9.76 (s, 1H) .: (M) ⁺ 320, (M-CH ₃ -H ₂ O) ⁺ 287.

N] (Z) -10,10,10-trifluoro-9-trifluoromethyl-5,5-dimethyl-9
-Trimethylsilanyloxy-dec-7-enal (Z) -10,10,10-trifluoro-9-trifluoromethyl-9-hydroxy-5,5-dimethyl-dec-7-enal 1.860 g (5 .80 mmol) in CH ₂
Dissolved in 20 ml of Cl ₂ , and at 0 degree, 71 mg (0.1 equivalent) of dimethylaminopyridine and 4.74 g of triethylamine
Sequential treatment with (8 equivalents) and 3.81 g (6 equivalents) of (CH ₃ ) ₃ SiCl. After stirring for 40 minutes at room temperature,
The reaction mixture was poured into crushed ice / hexane, the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. By flash chromatography (SiO ₂ , pentane / methyl acetate = 96/4) the title compound 1.
495 g was obtained as a colorless oil.

NMR: (1H.δ, TMS) 0.23 (s, 9H), 0.91
(s, 6H), 1.24 (m, 2H), 1.60 (m, 2H), 2.38 (br d, 2
H), 2.42 (t, 2H), 5.46 (br d, 1H), 5.97 (dt, 1H),
9.77 (s, 1H).

O] (1R, 3R) -1,3-bis- (te
rt-Butyl-dimethyl-silanyloxy) -5-((2
E, 9Z) -12,12,12-trifluoro-7,7
-Dimethyl-11-trifluoromethyl-11-trimethylsilanyloxy-dodeca-2,9-dienylidene)
-Cyclohexane Carefully dried (3R, 5R)-[2- [3,5-
1. Bis- (tert-butyldimethyl-silanyloxy) -cyclohexylidene] -ethyl] -diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) 2.
20 g (1.4 equivalents) of anhydrous tetrahydrofuran 25 ml
And n-butyllithium (1.55
M, hexane) 2.48 ml. After 10 minutes, it was dissolved in 10 ml of anhydrous tetrahydrofuran (Z) -10,1.
0,10-trifluoro-9-trifluoromethyl-
1.080 g of 5,5-dimethyl-9-trimethylsilanyloxy-dec-7-enal was added dropwise to the crimson solution. The mixture was maintained at -78 degrees for 0.75 hours, then N
Quenched with H ₄ Cl solution. Extract with ethyl acetate, wash with water, dry over sodium sulfate and evaporate the solvent.
The crude product remains, which is purified by short flash chromatography (SiO ₂ , hexane / ethyl acetate = 7/3) to give 2.35 g of diastereoisomeric β-hydroxy-phosphine oxide, which is as follows: Processed.

This intermediate was treated with anhydrous tetrahydrofuran 20
Dissolved in ml and treated at -15 degrees with approximately 4 equivalents of NaH (50% in mineral oil). The temperature was slowly raised to room temperature and stirring was continued until thin layer chromatography showed no starting material present (3 hours). Crushed ice / NH ₄ C
After quenching at l, the product was extracted with hexane, washed with water, dried over sodium sulfate and the solvent was removed. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 96/4) gave 1.08 g of the title compound as a colorless oil.

P] (1R, 3R) -5-[(2E, 9
Z) -12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-
Dodeca-2,9-dienylidene) -cyclohexane-
4.56 g (14.4 mmol) of tetrabutylammonium fluoride trihydrate in 20 ml of 1,3-diol tetrahydrofuran
Was carefully dried by passing through 5 g of 3Å molecular sieves and stirring at room temperature for 2 hours. This solution was then prepared above (1R, 3R) -1,3-bis-
(Tert-butyl-dimethyl-silanyloxy) -5-
((2E, 9Z) -12,12,12-trifluoro-
7,7-Dimethyl-11-trifluoromethyl-11-
Trimethylsilanyloxy-dodeca-2,9-dienylidene) -cyclohexane (1.08 g, 1.60 mmol) was added and the mixture was maintained at 40 ° C. for 2 hours. The reaction mixture was then poured into crushed ice / NH ₄ Cl, extracted twice with ethyl acetate, washed with water, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 35/65) gave 699 mg of the title compound as a colorless varnish. Usually, this product is contaminated with a small amount of 2Z isomer, which is analyzed by HPLC (RAININ Microsorb Si 80-120-C5,
Solvent: hexane / isopropanol 9/1) can be removed and isolated.

MS: (M) ⁺ 444, (MH ₂ O) ⁺ 426. (cm ^-1 ): 335
0, 2940, 1665, 1304, 1265, 1217, 1172, 1147, 966 .:
(1H, δ, TMS) 0.89 (s, 6H). 1.2-1.5 (m, 4H), 1.60
(br s, 2H, OH), 1.88 (t, 2H), 2.0-2.7 (m, 8H), 3.9
4 (br s, 1H, OH), 4.10 (m, 2H), 5.46 (brd, 1H), 5.
69 (dt, 1H), 5.97-6.13 (m, 2H), 6.26 (m, 1H).

B. (1R, 3R) -5-[(2E, 9
Z) -12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-
Dodeca-2,9-dienylidene) -cyclohexane-
Alternative Preparation Method of 1,3-Diol a] 5,5-Dimethyl-oxepan-2-ol 5,5-dimethyl-oxepan-2-one 15.12 g
(106.3 mmol) of anhydrous tetrahydrofuran 500 ml
, And cooled to -78 degrees. Diisobutylaluminum hydride (1.
173 ml (0M, hexane) was added slowly with a dropping funnel. After 90 minutes, excess reagent was destroyed by adding 4 ml of methanol at −78 ° C. followed by quenching with ice / NH ₄ Cl solution. Extract twice with ether, wash with HCl and NaHCO ₃ , dry over sodium sulfate,
Evaporation of solvent left a crude product which was used as such in the next step. According to ¹ H NMR, it was present as a mixture of lactol and hydroxy-aldehyde.

B] 3,3-Dimethyl-hept-6-en-1-ol 5,5-dimethyl-oxepan-2-ol 12.24
g (84.8 mmol) of anhydrous tetrahydrofuran 375 ml
Dissolved in. Methyltriphenylphosphonium bromide (75.81 g, 2.5 equivalents) was added and the reaction vessel was cooled to -16.
Cooled once. 23.81 g potassium tert-butyrate
(2.5 eq) was added in one portion (slight exotherm) and the reaction mixture was stirred at room temperature for 4.5 g. Poured into crushed ice / NH ₄ Cl solution, extracted twice with ether, washed with brine, dried over sodium sulphate and solvent evaporated to leave a crude product which was flash chromatographed (Si
Purification with O ₂ , hexane / ethyl acetate = 8/2) gave 9.95 g of the title compound as a yellowish oil.

[0084] _{MS: (MH 2 O-CH} 3) + 109 .: (1H, δ, TMS) 0.
85 (s, 6H), 1.23 (m. 2H), 1.38 (t, 2H), 1.99 (m, 2
H), 3.42 (m, 2H), 4.22 (t, OH), 4.87 (br d, 1H),
5.00 (br d, 1H), 5.82 (m, 1H).

C] 3,3-Dimethyl-hept-6-enal 11.95 ml (168 mmol) of anhydrous dimethyl sulfoxide dissolved in 45 ml of anhydrous CH ₂ Cl ₂ were added to 200 ml of CH ₂ Cl _2.
The Swern reagent was prepared by slowly adding (exothermic) to a solution of 6.60 ml (76.8 mmol) of oxalyl chloride in medium. After 30 minutes, dissolved in 70 ml of CH ₂ Cl ₂ 3,3
-Dimethyl-hept-6-en-1-ol 9.95 g
(69.9 mmol) was added slowly (vigorous exotherm).
After 1 hour at -60 ° C, 33.0 ml of triethylamine (2
(37 mmol) was added dropwise and the temperature reached 0 ° C. Crushed ice
The reaction is quenched by pouring into HCl and CH ₂
Extracted twice with Cl ₂ , washed with Na ₂ CO ₃ solution, dried over sodium sulphate and reduced to approximately 100 ml. Due to its high volatility, this product was directly processed as follows.

D] 1,1-Dibromo-4,4-dimethyl-octa-1,7-diene 34.80 g (10) of CBr _{4 in} 285 ml of anhydrous CH ₂ Cl ₂
4.9 mmol) was treated at −18 ° C. with 55.04 g (209.8 mmol) triphenylphosphine. After 10 minutes, the aldehyde solution prepared above (<69 mmol) was added dropwise and the mixture was kept at -10 ° C for 15 minutes. Then, the reaction mixture was separated twice between hexane and ethanol / water = 8/2, the upper layer was washed with ethanol / water = 8/2, dried over sodium sulfate, and the solvent was removed. Flash chromatography (SiO ₂ , hexane) yielded 16.31 g of the title compound as a colorless oil.

MS: (MC ₄ H ₇ ) ⁺ 241 .: (1H, δ, TMS) 0.92
(s, 6H), 1.31 (m, 2H), 2.02 (m, 4H), 4.94 (br d, 1
H), 5.02 (br d, 1H), 5.82 (m, 1H), 6.42 (t, 1H).

E] 1,1,1-Trifluoro-2-trifluoromethyl-6,6-dimethyl-dec-9-ene-
3-in-2-ol 1,1-dibromo-4,4-dimethyl-octa-1,7
Dissolve 16.31 g (55.09 mmol) of diene in 240 ml of anhydrous tetrahydrofuran and, at -74 degrees, 107 ml of n-butyllithium (1.55M, hexane, 3 eq).
Processed in. After 30 minutes, a large excess of hexafluoro-
Introduce acetone (about 38g) into the reaction flask and
Reacted for hours. The temperature was raised to −10 ° C. and the reaction was quenched by pouring into crushed ice. Extract twice with ether, wash with NH ₄ Cl, dry over sodium sulfate,
Evaporation of the solvent left a crude product which was purified by flash chromatography (SiO ₂ , hexane / ethyl acetate = 9/1) to give the title compound 20.1
8 g was obtained as a colorless oil.

[0089] _{MS: (M-CH 3)} + 287 .: (1H, δ, TMS) 0.99
(s, 6H), 1.38 (m, 2H), 2.02 (m, 2H), 2.19 (s, 2H),
3.19 (s, OH), 4.95 (br d, 1H), 5.02 (br d, 1H),
5.81 (m, 1H).

F] 10,10,10-trifluoro-9
-Trifluoromethyl-5,5-dimethyl-dec-7-
In-l, 9-diol According to standard procedure (J. Am. Chem. Soc. 94, 3567 (1972)), 18.6 mmol of the thexyl-borane solution (0.5 M, tetrahydrofuran) was prepared. 1,1,1-trifluoro-2 dissolved in 37 ml of tetrahydrofuran
-Trifluoromethyl-6,6-dimethyl-deca-9-
En-3-in-2-ol 6.50 g (16.9 mmo
l) was added dropwise at 0 ° C. and reacted at 0 ° C. for 10 minutes and at room temperature for 0.5 hours. 14.8 g H ₂ O ₂ (35%) and Na
19.3 g of OH (28%) was added carefully (vigorous exotherm) and the mixture was vigorously stirred for 30 minutes at 35-40 degrees. The reaction mixture was then poured into crushed ice / NH ₄ Cl solution, extracted twice with ether, washed with bisulfite solution and brine, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO
₂ , hexane / ethyl acetate = 7/3) to give 4.09 g of the captioned compound as a colorless oil.

G] (Z) -10,10,10-trifluoro-9-trifluoromethyl-5,5-dimethyl-dec-7-ene-1,9-diol 10,10,10-trifluoro- 4.09 g (12.77 mmol) of 9-trifluoromethyl-5,5-dimethyl-dec-7-yne-1,9-diol was mixed with 80 m of ethyl acetate.
Dissolve in l, Pd / C for 110 minutes at room temperature and atmospheric pressure
Hydrogenated with 0.80 g (10%). The reaction mixture was filtered through a pad of Celite to remove the solvent. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 8/2) gave 3.10 g of the title compound which is identical to the product obtained in Example 1 / Step l.

Example 2 (Z)-(1R, 3S) -4-methylene-5-[(2
E, 9Z) -12,12,12-trifluoro-11-
Hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene] -cyclohexane-1,3-diol as in Preparation Example 1, but in step o] (Z)-(3S, 5
R)-[2- [3,5-Bis- (tert-butyldimethyl-silanyloxy) -2-methylene-cyclohexylidene] -ethyl] -diphenyl-phosphine oxide, using (Z)-(1R, 3S) -4-methylene-5-
[(2E, 9Z) -12,12,12-trifluoro-
11-Hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene] -cyclohexane-1,3-diol was prepared as a colorless oil.

MS: (M) ⁺ 456, (MH ₂ O) ⁺ 438. (cm ^-1 ): 334
0, 2940, 1308, 1264, 1211, 1170, 1145, 964 .: (1H,
δ, TMS) 0.88 (s, 6H), 1.15-1.6 (m, 4H), 1.60 (br
s, 2H.OH), 1.97 (t, 2H), 2.0-2.65 (m, 6H), 3.75
(br s, 1H, OH), 4.24 (m, 1H), 4.44 (br t, 1H), 5.0
0 (brs, 1H), 5.32 (br s, 1H), 5.45 (br d, 1H), 5.7
0 (dt, 1H), 6.00-6.14 (m, 2H), 6.39 (m, 1H).

Example 3 (Z)-(1R, 3S) -5-((2E, 9E) -1
2,12,12-Trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-
Preparation of 2,9-dienylidene) -4-methylene-cyclohexane-1,3-diol a] (E) -1,1,1-trifluoro-2-trifluoromethyl-6,6-dimethyl-10- ( Tetrahydro-pyran-2-yloxy) -dec-3-en-2-ol 191 mg (5 eq) LiAlH ₄ was suspended in 18 ml anhydrous tetrahydrofuran and cooled to 0 °. After adding 271 mg (5 equivalents) of sodium methylate, 1,1,1
-Trifluoro-2-trifluoromethyl-6,6-dimethyl-10- (tetrahydro-pyran-2-yloxy) -dec-3-yn-2-ol 408 mg (1.01
mmol) (Example 1 step j]) in 11 ml of tetrahydrofuran was added. The mixture was heated at reflux for 2 hours, then at 0 ° C. 1.6 ml water and 2N NaOH.
Carefully quench with 1.6 ml. Then 27 ml of ether were added and the mixture was stirred vigorously to complete the hydrolysis of the Al salt. Drying over magnesium sulphate and evaporation of the solvent left 334 mg of the title product of sufficient purity as a colorless oil for use in the next step. MS: (MH) ⁺ 405

B] (E) -10,10,10-Trifluoro-9-trifluoromethyl-5,5-dimethyl-dec-7-ene-1,9-diol (E) -1,1,1 -Trifluoro-2-trifluoromethyl-6,6-dimethyl-10- (tetrahydro-pyran-2-yloxy) -dec-3-en-2-ol 334 mg (0.821 mmol) was dissolved in 6 ml methanol, Pyridinium- (toluene-4-sulfonate) 2
Treated with 1 mg (0.1 eq) and kept at room temperature for 24 hours. The reaction mixture was then poured into crushed ice / Na ₂ CO ₃ , extracted twice with ether, washed with brine, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate =
7/3) gave 224 mg of the title compound as a colorless oil.

MS: (M-CH ₃ -H ₂ O) ⁺ 289 .: (1H, δ, TMS) 0.
90 (s. 6H), 1.2-1.6 (m, 6H + 2OH), 2.06 (br d, 2H),
3.67 (t, 2H), 4.15 (br s, 1OH), 5.57 (d, 1H, J = 1
6), 6.32 (dt, 1H, J = 16, J = 8).

C] (E) -10,10,10-trifluoro-9-trifluoromethyl-9-hydroxy-5,
5-Dimethyl-dec-7-enal (E) -10,10,10-trifluoro-9-trifluoromethyl-5,5-dimethyl-dec-7-ene-
It was oxidized by dichromate 1.84 g (3.8 eq) and allowed overnight reaction - 1,9 diol 417mg of (1.294mmol), at room temperature, CH ₂ Cl ₂ 40ml pyridinium. Filter through a pad of silica gel,
The solvent was removed and flash chromatography (SiO 2
₂ , hexane / ethyl acetate = 8/2) was carried out to obtain 333 mg of the captioned compound as a colorless oily substance. _{MS: (M-CH 3 -H} 2 O) + 289

D] (3E, 10E) -12-[(Z)-
(3S, 5R) -3,5-bis- (tert-butyl-dimethyl-silanyloxy) -2-methylene-cyclohexylidene] -1,1,1-trifluoro-6,6-dimethyl-2-trifluoro Methyl-dodeca-3,10-dien-2-ol Carefully dried (Z)-(3S, 5R)-[2-
[3,5-bis- (tert-butyldimethyl-silanyloxy) -2-methylene-cyclohexylidene] -ethyl] -diphenyl-phosphine oxide 1.515 g
(2.5 eq) was dissolved in 9 ml of anhydrous tetrahydrofuran and treated at -78 ° C with 1.96 ml of n-butyllithium (1.5M, hexane). After 20 minutes, (E) -10,10,10-trifluoro-9-trifluoromethyl-9-hydroxy-dissolved in 4 ml of tetrahydrofuran.
333 mg of 5,5-dimethyl-dec-7-enal (1.
(04 mmol) was added dropwise to the crimson solution and the mixture was maintained at -78 ° C for 1 hour and then quenched with NH ₄ Cl solution. Extraction with ether, washing with water, drying over sodium sulphate and evaporation of the solvent left a crude product which was flash chromatographed (SiO ₂ , hexane / ethyl acetate = 7 /
(3, then ethyl acetate) gives 857 mg of diastereoisomeric β-hydroxy-phosphine oxide in addition to the excess of starting phosphine oxide in the more polar fraction, which is treated as follows: did.

This intermediate was mixed with 8 ml of anhydrous tetrahydrofuran.
At 0 ° C. and about 4 equivalents of NaH (50 in mineral oil).
%). The temperature was slowly raised to room temperature and stirring was continued until thin layer chromatography showed no starting material present (1.5 hours). After quenching with crushed ice, the product was extracted with ether, washed with water, dried over sodium sulfate, and the solvent was removed. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 95 /
According to 5), 151 mg of the captioned compound was obtained as a colorless oil.

E] (Z)-(1R, 3S) -5-((2
E, 9E) -12,12,12-trifluoro-11-
Trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-2,9-dienylidene) -4-methylene-cyclohexane-1,3-diol Tetrabutylammonium fluoride trihydrate 0.83 g in 3.5 ml tetrahydrofuran (2.60mmo
l) was carefully dried by passing through 1.05 g of 3Å molecular sieves and stirring at room temperature for 2 hours. This solution was then prepared above (3E, 10E) -12.
-[(Z)-(3S, 5R) -3,5-bis- (tert-
Butyl-dimethyl-silanyloxy) -2-methylene-
Cyclohexylidene] -1,1,1-trifluoro-
6,6-Dimethyl-2-trifluoromethyl-dodeca
Add to 151 mg 3,10-dien-2-ol and maintain at 45 ° C for 1.5 hours. The reaction mixture was then poured onto crushed ice, extracted twice with ether, washed with water, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 4 /
According to 6), 76 mg of the captioned compound was obtained as a colorless oil.

MS: (M) + 456, (MH ₂ O) ⁺ 438. (cm ^-1 ): 336
0, 2980, 1308, 1294, 1211, 1179, 1146, 959 .: (1H,
δ, TMS) 0.86 (s, 6H), 1.3-2.2 (m, 9H + 3OH), 2.29 (d
d, 1H), 2.45 (t, 1H), 2.57 (dd, 1H), 4.24 (m, 1H),
4.43 (br t, 1H), 5.00 (br s, 1H), 5.31 (br s, 1H),
5.55 (br d, 1H, J = 16), 5.71 (dt, 1H), 6.03 (br d,
1H), 6.29 (dt, 1H), 6.38 (dd, 1H).

Example 4 (1R, 3R) -5-[(2E, 9E) -12,12,
12-trifluoro-11-trifluoromethyl-11
Preparation of -Hydroxy-7,7-dimethyl-dodeca-2,9-dienylidene] -cyclohexane-1,3-diol a] (E) -10,10,10-trifluoro-9-trifluoromethyl-5, 5-Dimethyl-9-trimethylsilanyloxy-dec-7-enal (E) -10,10,10-trifluoro-9-trifluoromethyl-9-hydroxy-5,5-dimethyl-dec-7-enal 245 mg (0.765 mmol) (Example 3)
c)) is dissolved in 3.6 ml of CH ₂ Cl ₂ and at 0 ° C.,
Dimethylaminopyridine 9.3 mg (0.1 equivalent), triethylamine 0.853 ml (8 equivalent) and (CH ₃ ) ₃
Sequential treatment with 0.581 ml of SiCl (6 equiv.).
After stirring for 30 minutes at ambient temperature, the reaction mixture is crushed on ice /
Poured into ether, the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 95
/ 5) gave 275 mg of the very unstable title compound as a pale yellow oil.

B] (1R, 3R) -5-[(2E, 9
E) -12-Trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-2,
9-Dienylidene] -cyclohexane-1,3-diol Carefully dried (3R, 5R)-[2- [3,5-
Bis- (tert-butyldimethyl-silanyloxy) -cyclohexylidene] -ethyl] -diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) 0.
633 g (1.6 equivalents) of anhydrous tetrahydrofuran 6 ml
, And at −78 ° C., sec-butyllithium (1.3
M, cyclohexane) 1.15 ml. After 20 minutes, it was dissolved in 2 ml of anhydrous tetrahydrofuran (E) -1.
272 mg of 0,10,10-trifluoro-9-trifluoromethyl-5,5-dimethyl-9-trimethylsilanyloxy-dec-7-enal were added to the crimson solution. The mixture was kept at -78 degrees for 1 hour and then NH ₄ C
The solution was quenched. Extraction twice with ether, washing with water, drying over sodium sulphate and evaporation of the solvent leave a crude product which is purified by short flash chromatography (SiO ₂ , hexane / ethyl acetate = 7/3). 580 mg of diastereoisomeric β-hydroxy-phosphine oxide were obtained as a white foam, which was treated as follows.

This intermediate was mixed with 6 ml of anhydrous tetrahydrofuran.
At 0 ° C. and about 4 equivalents of NaH (50 in mineral oil).
%). The temperature was slowly raised to room temperature and stirring was continued until thin layer chromatography showed no starting material present (1.5 hours). After quenching with crushed ice / NH ₄ Cl, the product was extracted with ether, washed with water, dried over sodium sulfate and the solvent was removed. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 95/5) gave 273 mg of triene as a colorless oil, which was deprotected as follows.

1.40 g of tetrabutylammonium fluoride trihydrate (4.
45 mmol) was carefully dried by passing through 1.78 g of 3Å molecular sieves and stirring at room temperature for 2 hours. This solution was then prepared above (1R, 3R)-
1,3-Bis- (tert-butyl-dimethyl-silanyloxy) -5-((2E, 9E) -12,12,12-trifluoro-7,7-dimethyl-11-trifluoromethyl-11-trimethylsila Nyloxy-dodeca-2,
270 mg (0.3-dienylidene) -cyclohexane (0.3
71 mmol) and maintained at 40 degrees for 1.5 hours. The reaction mixture was then poured into crushed ice / NH ₄ Cl, extracted twice with ether, washed with water, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 25/75) gave 165 mg of the title compound as a colorless oil.
Usually the product is contaminated with a small amount of 2Z isomer, which can be removed by HPLC.

MS: (M) + 444, (MH ₂ O) ⁺ 426 .: (1H, δ, T
MS) 0.87 (s, 6H), 1.2-2.7 (m, 14H + 3OH), 4.10 (m, 2
H), 5.54 (d, 1H, J = 15.5), 5.67 (dt, 1H), 6.00 (br
d, 1H), 6.2-6.4 (m, 2H).

Example 5 (1R, 3R) -5-[(2E) -12,12,12-
Trifluoro-11-hydroxy-7,7-dimethyl-
11-trifluoromethyl-dodeca-2-anylidene)
-Preparation of cyclohexane-1,3-diol a] 10,10,10-Trifluoro-9-trifluoromethyl-5,5-dimethyl-decane-1,9-diol 10,10,10-trifluoro-9 -Trifluoromethyl-5,5-dimethyl-dec-7-yne-1,9-diol 1.00 g (3.12 mmol) (Example 1 step k])
At a pressure of 9 bar H ₂ and room temperature for 20 hours, Pd / C
Hydrogenated with 1 g (10%). Filtration through a pad of Celite and evaporation of the solvent gave the title compound 0.83
g left. This was directly used in the next step.

NMR: (1H, δ, TMS) 0.81 (s, 6H), 1.1-1.
5 (m, 10H + OH), 1.80 (br t, 2H), 3.38 (t, 2H), 7.71
(s, 1H).

B] 10,10,10-trifluoro-9
-Trifluoromethyl-9-hydroxy-5,5-dimethyl-decanal 10,10,10-trifluoro-9-trifluoromethyl-5,5-dimethyl-decane-1,9-diol 8
30 mg (2.56 mmol) of CH ₂ Cl ₂ 79 ml at room temperature
Oxidized by reaction with 3.64 g (3.8 eq) of medium pyridinium-dichromate overnight. Filtration through a pad of silica gel, removal of the solvent and flash chromatography (SiO ₂ , hexane / ethyl acetate = 8/2) gave 675 mg of the title compound as a colorless oil.

NMR: (1H, δ, TMS) 0.83 (s, 6H), 1.05-
1.2 (m, 4H), 1.3-1.55 (m, 4H), 1.80 (br t, 2H), 2.4
0 (br t, 2H), 7.71 (s, 1H), 9.66 (br s, 1H).

C] 10,10,10-trifluoro-9
-Trifluoromethyl-5,5-dimethyl-9-trimethylsilanyloxy-decanal 10,10,10-trifluoro-9-trifluoromethyl-9-hydroxy-5,5-dimethyl-decanal 672 mg (2.085 mmol) ) In 10 ml CH ₂ Cl ₂ and at 0 ° C. 26 mg dimethylaminopyridine (0.1 eq), 2.32 ml NEt ₃ (8 eq) and (CH ₃ ) ₃
Sequential treatment with 1.58 ml (6 eq) of SiCl. After stirring for 30 minutes at ambient temperature, the reaction mixture was quenched by pouring into crushed ice / ether, the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / methyl acetate = 96/4) gave 717 mg of the unstable title compound as a pale yellow oil.

NMR: (1H, δ, TMS) 0.19 (s, 9H), 0.83
(s, 6H), 1.05-1.55 (m, 8H) 185 (brt, 2H), 2.39 (br
t, 2H), 9.64 (br s, 1H).

D] (1R, 3R) -5-[(2E) -1
2,12,12-trifluoro-11-hydroxy-
7,7-Dimethyl-11-trifluoromethyl-dodeca-2-enylidene) -cyclohexane-1,3-diol Carefully dried (3R, 5R)-[2- [3,5-
Bis- (tert-butyldimethyl-silanyloxy) -cyclohexylidene] -ethyl] -diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) 0.
709 g (1.4 equivalents) of anhydrous tetrahydrofuran 5 ml
, And at −78 ° C., sec-butyllithium (1.3
M, cyclohexane) 1.325 ml. After 20 minutes at this temperature, 347 mg (0.880 mmol) of 10,10,10-trifluoro-9-trifluoromethyl-5,5-dimethyl-9-trimethylsilanyloxy-decanal, dissolved in 2 ml of anhydrous tetrahydrofuran, were taken deep. Dropwise into the red solution. After the mixture was maintained at -78 ° for 1.5 hours, then quenched with solution _of NH ₄ Cl. Extraction twice with ether, washing with water, drying over sodium sulphate and evaporation of the solvent left a crude product which was subjected to short flash chromatography (SiO ₂ , hexane / ethyl acetate = 7).
Purification by 3/3) gave 725 mg of diastereoisomeric β-hydroxy-phosphine oxide, which was treated as follows.

This intermediate was treated with anhydrous tetrahydrofuran 6.
Dissolved in 1 ml and treated at 0 ° with approximately 4 equivalents of NaH (50% in mineral oil). Slowly raise the temperature to room temperature,
Stirring was continued for 1 hour. After quenching with crushed ice / NH ₄ Cl, the product was extracted twice with ether, washed with water, dried over sodium sulfate and the solvent was removed. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 96
/ 4) gave 285 mg of triene as a yellowish oil, which was deprotected as follows.

1.50 g of tetrabutylammonium fluoride trihydrate in 6.5 ml of tetrahydrofuran
(4.76 mmol) of 3Å molecular sieve 1.91 g
It was carefully dried by stirring through the flask at room temperature for 2 hours. This solution was then prepared above (1R, 3
R) -1,3-Bis- (tert-butyl-dimethyl-silanyloxy) -5-((E) -12,12,12-trifluoro-7,7-dimethyl-11-trifluoromethyl-11-trimethyl Silanyloxy-dodeca-2-enylidene) -cyclohexane 283 mg (0.378 mmo
In addition to l), it was maintained at 40 degrees for 2 hours. The reaction mixture was then poured into crushed ice / NH ₄ Cl, extracted twice with ether, washed with water, dried over sodium sulphate and evaporated to dryness. Flash chromatography (Si
O ₂ and hexane / ethyl acetate = 1/1) gave 177 mg of the captioned compound as a colorless oil. Usually the product is contaminated with a small amount of Z isomer, which can be removed by HPLC.

MS: (M) ⁺ 446, (MH ₂ O) ⁺ 428. (cm ^-1 ): 334
5, 2958, 1628, 1470, 1366, 1213, 1180, 1142, 1047,
967, 936 .: (1H, δ, TMS) 0.85 (s, 6H), 1.1-2.4 (m,
16H + 2OH), 3.75 (br s, OH), 2.47 (dd, 1H), 2.63 (d
d, 1H), 4.07 (m, 2H), 5.70 (dt, 1H), 6.01 (d, 1H),
6.26 (br dd. 1H).

Example 6 (Z)-(1R, 3S) -5-[(2E) -12,1
2,12-trifluoro-11-hydroxy-7,7-
Dimethyl-11-trifluoromethyl-dodeca-2-anylidene] -4-methylene-cyclohexane-1,3-
As in diol example 5, except that in step d] (Z)-(3S, 5
R)-[2- [3,5-Bis- (tert-butyldimethyl-silanyloxy) -2-methylene-cyclohexylidene] -ethyl] -diphenyl-phosphine oxide.

MS (M) + 458, (MH ₂ O) ⁺ 440. (cm ^-1 ): 334
8, 2958, 1640, 1470, 1367, 1212, 1178, 1143, 1049,
976, 923 .: (1H, δ, TMS) 0.84 (s, 6H). 1.15-2.1
(m, 12H + 2OH), 1.97 (t, 2H), 2.26 (dd, 1H), 2.59 (d
d, 1H), 3.37 (br s, OH), 4.23 (m, 1H), 4.43 (m, 1
H), 5.00 (br s, 1H), 5.31 (br s, 1H), 5.73 (dt, 1
H), 6.03 (d, 1H), 6.38 (brdd, 1H).

Example 7 (E)-(1R, 3R) -5- [12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-1
1-Trifluoromethyl-dodeca-2-ene-9-ynylidene] -cyclohexane-1,3-diol Prepared as a colorless oil as described in Example 1, but omitting the hydrogenation step 1]. .

[0120] CI-MS: (M + NH 4) + 460 .: (1H, δ, TMS) 0.9
6 (s, 6H), 1.2-2.6 (m, 12H + 3OH), 2.16 (s, 2H), 4.1
1 (m, 2H), 5.66 (dt, 1H), 6.03 (d, 1H), 6.27 (br d
d, 1H).

Example 8 (Z)-(1R, 3S) -4-methylene-5-[(E)
-12,12,12-Trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2-ene-9-ylidene] -cyclohexane-
1,3-diol As described in Example 1, but omitting the hydrogenation step 1] and in step o] (Z)-(3S, 5R)-[2- [3,3
5-bis- (tert-butyldimethyl-silanyloxy)
Prepared as a colorless oil using 2-methylene-cyclohexylidene] -ethyl] -diphenyl-phosphine oxide.

MS: (M) ⁺ 454, (MH ₂ O) ⁺ 436 .: (1H, δ,
TMS) 0.95 (s. 6H), 1.2-1.5 (m, 4H + 2OH), 1.9-2.2
(m. 4H), 2.15 (s, 2H), 2.26 (dd, 1H), 2.60 (dd, 1
H), 4.23 (m, 1H), 4.46 (m, 1H), 5.01 (br s, 1H),
5.31 (br s, 1H), 5.73 (dt, 1H), 6.04 (d, 1H), 6.38
(br dd, 1H).

Example 9 (Z)-(S) -4-methylene-3-[(E) -12,
12,12-trifluoro-11-hydroxy-7,7
-Dimethyl-11-trifluoromethyl-dodeca-2-
En-9-Inylidene] -cyclohexan-1-ol As described in Example 1, but omitting the hydrogenation step 1] and in step o] (Z)-(5S)-[2- [5- (tert
-Butyldimethyl-silanyloxy) -2-methylene-
Prepared as a colorless oil using cyclohexylidene] -ethyl] -diphenyl-phosphine oxide.

MS: (M) ⁺ 438, (MH ₂ O) ⁺ 420 .: (1H, δ,
TMS) 0.96 (s. 6H), 1.2-2.5 (m, 11H + 2OH), 2.15 (s,
2H), 2.54 (dd, 1H), 3.96 (m, 1H), 4.83 (br s, 1H),
5.05 (br s. 1H), 5.67 (dt, 1H), 5.89 (d, 1H), 6.39
(br dd, 1H).

Example 10 (10E, 12Z)-(S) -12- (5-Hydroxy-2-methylene-cyclohexylidene) -6,6-dimethyl-2-methyl-dodeca-10-en-3-yne -2
Preparation of -ol a] 2,6,6-trimethyl-10- (tetrahydro-
Pyran-2-yloxy) -dec-3-yn-2-ol 2- (8,8-dibromo-5,5-dimethyl-oct-
3.0-g 7-enyloxy) -tetrahydro-pyran
(11.44 mmol) (Example 1 / step i]) was dissolved in 33 ml of anhydrous tetrahydrofuran and at −78 ° C. 15.12 ml of n-butyllithium (1.55M, hexane, 3 eq).
Processed in. After 50 minutes, 2.77 ml of acetone (5 equivalents) dissolved in 10 ml of tetrahydrofuran were added dropwise and the mixture was kept at -78 ° for 30 minutes. Warmed to ambient temperature, poured into crushed ice, extracted twice with ether, washed with water, dried over sodium sulphate and evaporated the solvent to leave a crude product which was flash chromatographed (SiO ₂ ,
Purification by hexane / ethyl acetate = 85/15) gave 2.02 g of the title compound as a colorless oil. _{MS: (M-CH 3)} + 281

B] 5,5,9-Trimethyl-dec-7-
In-1,9-diol 2,6,6-trimethyl-10- (tetrahydro-pyran-2-yloxy) -dec-3-yn-2-ol 6
09 mg (2.05 mmol) was dissolved in 13.5 ml of methanol to give pyridinium- (toluene-4-sulfonate) 7
Treated with 6 mg (0.15 eq) and kept at room temperature overnight. The reaction mixture was then poured into crushed ice / Na ₂ CO ₃ , extracted twice with ethyl acetate, washed with brine, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 7/3) gave 413 mg of the title compound as a yellowish oil.

[0127] _{MS: (M-CH 3)} + 197 .: (1H, δ, TMS) 0.94
(s, 6H), 1.51 (s, 6H), 1.2-1.6 (m, 6H), 1.63 (brs,
2OH), 2.06 (s, 2H), 3.68 (t, 2H).

C] 9-Hydroxy-5,5,9-trimethyl-dec-7-inal 5,5,9-trimethyl-dec-7-yne-1,9-diol 410 mg (1.93 mmol) at room temperature And CH ₂ C
2.76 g of pyridinium-dichromate in 61 ml of l ₂
Oxidized by reacting with (3.8 eq) overnight. Filter through a pad of Celite, remove the solvent and perform flash chromatography (SiO ₂ , hexane / ethyl acetate = 8/2) to give the title compound 2
Obtained 45 mg as a colorless oil.

NMR: (1H, δ, TMS) 0.95 (s, 6H), 1.30
(m, 2H), 1.51 (s, 6H), 1.58 (m, 2H + OH), 2.07 (s, 2
H), 2.44 (td, 2H), 9.78 (t, 1H) .: (M-CH ₃ ) ⁺ 195.

D] 5,5,9-Trimethyl-9-trimethylsilanyloxy-dec-7-inal 9-hydroxy-5,5,9-trimethyl-dec-7-
242 mg (1.15 mmol) of Inal and 14 ml of CH ₂ Cl ₂
Dissolved in 1- (trimethylsilyl) imidazole 1.
Treated with 18 ml (7 eq). After 20 hours at room temperature, the mixture was poured onto crushed ice, extracted twice with ether, washed with water, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 95/5) gave 293 mg of the title compound as a colorless oil. CI-MS: (M + NH 4) + 300

E] (10E, 12Z)-(S) -12-
(5-Hydroxy-2-methylene-cyclohexylidene) -6,6-dimethyl-2-methyl-dodeca-10-
En-3-in-2-ol Carefully dried (Z)-(5S)-[2- [5-
(Tert-Butyldimethyl-silanyloxy) -2-methylene-cyclohexylidene] -ethyl] -diphenyl-
0.577 g (1.27 mmol) of phosphine oxide was dissolved in 8.5 ml of anhydrous tetrahydrofuran, and at -78 ° C.
n-Butyllithium (1.55M, hexane) 0.81
Treated with 9 ml. After 20 minutes at this temperature, 5,5,9-trimethyl-9-dissolved in 2 ml of anhydrous tetrahydrofuran.
Trimethylsilanyloxy-dec-7-inal 100
mg (0.354 mmol) was added dropwise to the crimson solution. 1 hour the mixture at -78 °, then maintained at -20 ° for 30 minutes and quenched with solution _of NH ₄ Cl. Extraction twice with ether, washing with brine, drying over sodium sulphate and evaporation of the solvent left a crude product which was purified by short flash chromatography (SiO ₂ , hexane / ethyl acetate = 7/3). Purification yielded 196 mg of diastereoisomeric β-hydroxy-phosphine oxide, which was treated as follows.

This intermediate was treated with anhydrous tetrahydrofuran 2.
Dissolved in 4 ml and treated at 0 ° with approximately 4 equivalents of NaH (50% in mineral oil). Slowly raise the temperature to room temperature,
Stirring was continued for 1 hour. After quenching with crushed ice / NH ₄ Cl, the product was extracted twice with ether, washed with NH ₄ Cl, dried over sodium sulfate and the solvent was removed. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 98.5 / 1.5) gave 81 mg of the triene as a colorless oil, which was deprotected as follows. ^{MS: (M) + 516,} (M-CH 3) + 501

0.776 g of tetrabutylammonium fluoride trihydrate in 2.5 ml of tetrahydrofuran
(2.46 mmol) of 3Å molecular sieve 0.98 g
It was carefully dried by stirring through an oven at room temperature for 1.5 hours. Next, 81 mg of this solution prepared above
(0.157 mmol) and maintained at 40 degrees for 2 hours.
The reaction mixture was then poured into crushed ice / NH ₄ Cl, extracted twice with ethyl acetate, washed with brine, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 7)
/ 3) gave 39 mg of the title compound as a colorless oil. Usually, this product is contaminated with a small amount of 10Z isomer, which can be removed by HPLC.

NMR: (1H, δ, TMS) 0.92 (s, 6H), 1.2-2.
5 (m, 11H + 2OH), 1.50 (s, 6H), 2.04 (s, 2H), 2.53 (d
d, 1H), 3.91 (m, 1H), 4.83 (br s, 1H), 5.05 (br s,
1H), 5.68 (dt, 1H), 5.89 (d, 1H), 6.41 (dd, 1H) .:
(MH ₂ O) ⁺ 312, (MH ₂ O-CH ₃ ) ⁺ 297.

Example 11 (10E)-(3R, 5R) -12- (3,5-dihydroxy-cyclohexylidene) -6,6-dimethyl-2
-Methyl-dodeca-10-en-3-yn-2-ol as in Preparation Example 10 but in step e] (3R, 5R)-
Using [2- [3,5-bis- (tert-butyldimethyl-silanyloxy) -cyclohexylidene] -ethyl] -diphenyl-phosphine oxide, (10E)-
(3R, 5R) -12- (3,5-Dihydroxy-cyclohexylidene) -6,6-dimethyl-2-methyl-dodeca-10-en-3-yn-2-ol as a yellowish oil It was prepared as a product.

NMR: (1H, δ, TMS) 0.93 (s, 6H), 1.2-2.
4 (m, 10H + 3OH), 1.50 (s, 6H), 2.04 (s, 2H), 2.48 (d
d, 1H), 2.63 (dd, 1H), 4.09 (m, 2H), 5.68 (dt, 1
H), 5.99 (d, 1H), 6.27 (dd, 1H) .: (MH ₂ O) ⁺ 316, (M
-H ₂ O-CH ₃ ) ⁺ 301.

Example 12 (Z)-(1S) -3-[(2E) -11-Hydroxy-7,7,11-trimethyl-dodeca-2-en-ylidene] -4-methylene-cyclohexan-1-ol Preparation a] 5,5,9-Trimethyl-decane-1,9-diol 5,5,9-trimethyl-dec-7-yne-1,9-diol 667 mg (3.14 mmol) (Example 10 / Step b) ])
30 ml of ethyl acetate containing 1 drop of triethylamine
(To avoid exclusion of water) and hydrogenated with 300 mg Pd / C (5%) for 180 minutes at room temperature and atmospheric pressure. The reaction mixture was filtered through a pad of Celite and the solvent removed to leave 620 mg of the title compound as a colorless oil. This was directly used in the next step.

NMR: (1H, δ, TMS) 0.85 (s, 6H), 1.1-1.
6 (m, 12H + 2OH), 1.22 (s, 6H), 3.63 (t, 2H) .: (MC
^{_{H 3) + 201, (M}} -HO) + 199.

B] 9-hydroxy-5,5,9-trimethyl-decaneal 5,5,9-trimethyl-decane-1,9-diol 6
60 mg (3.05 mmol) at room temperature of CH ₂ Cl ₂ 97 ml
Oxidized by reacting with 4.36 g (3.8 eq) of medium pyridinium-dichromate overnight. Filtration through a pad of silica gel, solvent removal and flash chromatography (SiO ₂ , hexane / ethyl acetate = 7/3) gave 452 mg of the title compound as a colorless oil.

NMR: (1H.δ, TMS) 0.87 (s, 6H), 1.1-1.
7 (m, 10H + OH), 1.22 (s, 6H), 2.41 (td, 2H), 9.77
(t, 1H) .: (M-CH ₃ ) ⁺ 199.

C] 5,5,9-Trimethyl-9-trimethylsilanyloxy-decanal 9-hydroxy-5,5,9-trimethyl-decanal 450 mg (2.10 mmol) was dissolved in 26 ml CH ₂ Cl ₂ , 1- (trimethylsilyl) imidazole 2.15 ml
(7 equivalents). After 20 hours at room temperature, the mixture was poured onto crushed ice, extracted twice with ether, washed with water, dried over sodium sulphate and evaporated to dryness. This crude product is formed by the nucleophilic addition of imidazole,
It was found to be a mixture of the target aldehyde and the corresponding semi-aminal. Hexane / ethyl acetate = 9/15
The imidazole was cleaved by dissolving in 0 ml and passing through 15 g of silica gel and stirring for 2.5 hours. Filtration, solvent evaporation and flash chromatography (SiO ₂ , hexane / ethyl acetate = 97/3) gave 566 mg of the title compound as a colorless oil.

NMR: (1H, δ, TMS) 0.10 (s, 9H), 0.86
(s, 6H), 1.1-1.7 (m, 10H), 1.20 (s, 6H), 2.40 (td,
2H), 9.77 (t, 1H) .: (M-CH ₃ ) ⁺ 271.

D] (Z)-(1S) -3-[(2E)-
11-Hydroxy-7,7,11-trimethyl-dodeca-2-en-ylidene] -4-methylene-cyclohexan-1-ol Carefully dried (Z)-(5S)-[2- [5-
(Tert-Butyldimethyl-silanyloxy) -2-methylene-cyclohexylidene] -ethyl] -diphenyl-
0.483 g (1.07 mmol) of phosphine oxide was dissolved in 5 ml of anhydrous tetrahydrofuran, and n-
Butyllithium (1.55M, hexane) 0.800 ml
Processed in. After 20 minutes at this temperature, 181 mg (0.63) of 5,5,9-trimethyl-9-trimethylsilanyloxy-decanal dissolved in 2 ml of anhydrous tetrahydrofuran.
2 mmol) was added dropwise to the deep red solution. After the mixture was maintained at -78 ° for 40 minutes and quenched with solution _of NH ₄ Cl.
Extraction twice with ethyl acetate, washing with brine, drying over sodium sulphate and evaporation of the solvent left a crude product which was subjected to short flash chromatography (SiO 2).
₂ , hexane / ethyl acetate = 7/3) to give 466 mg of diastereoisomeric β-hydroxy-phosphine oxide, which was treated as follows.

This intermediate was mixed with 6 ml of anhydrous tetrahydrofuran.
At 0 ° C. and about 4 equivalents of NaH (50 in mineral oil).
%). The temperature was slowly raised to room temperature and stirring was continued for 40 minutes. After quenching with crushed ice / NH ₄ Cl, the product was extracted twice with ether, washed with brine, dried over sodium sulfate and the solvent was removed. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 99/1) gave 198 mg of the triene as a colorless oil, which was deprotected as follows. MS: (M) ⁺ 520

1.88 g of tetrabutylammonium fluoride trihydrate (5.
96 mmol) was carefully dried by passing through 2.38 g of 3Å molecular sieves and stirring at room temperature for 2 hours. This solution was then added to 198 mg (0.3
8 mmol) and maintained at 40 degrees for 2 hours. The reaction mixture was then poured onto crushed ice, extracted twice with ethyl acetate, washed with brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO
₂ , hexane / ethyl acetate = 4/6) to give 120 mg of the captioned compound as a colorless oil. Usually the product is contaminated with a small amount of 2Z isomer, which can be removed by HPLC.

NMR: (1H, δ, TMS) 0.83 (s, 6H), 1.10-
2.5 (m, 17H + 2OH), 1.22 (s, 6H), 2.53 (dd, 1H), 3.9
1 (m, 1H), 4.83 (br s, 1H), 5.05 (br s, 1H), 5.68
(dt, 1H), 5.89 (d, 1H), 6.40 (dd, 1H) .: (M) ⁺ 334,
(MH ₂ O) + 316, (M-2H ₂ O) ⁺ 298. (cm ^-1 ): 3362, 2937, 2
867, 1635, 1470, 1364, 1053.

Example 13 (Z)-(1R, 3S) -5-[(E) -11-Hydroxy-7,7,11-trimethyl-dodeca-2-enylidene] -4-methylene-cyclohexane-1,3 As in Preparation Example 12 for diol, except that in step d] (Z)-(3S, 5
R)-[2- [3,5-Bis- (tert-butyldimethyl-silanyloxy) -2-methylene-cyclohexylidene] -ethyl] -diphenyl-phosphine oxide, using (Z)-(1R, 3S) -5-[(E) -11
-Hydroxy-7,7,11-trimethyl-dodeca-2
-Anylidene] -4-methylene-cyclohexane-1,
The 3-diol was prepared as a colorless oil.

NMR: (1H, δ, TMS) 0.84 (s, 6H), 1.10-
2.15 (m, 14H + 3OH), 1.22 (s, 6H), 2.26 (dd, 1H), 2.
57 (dd, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5.01 (br
s, 1H), 5.31 (br s, 1H), 5.74 (dt, 1H), 6.03 (d, 1
H), 6.38 (dd, 1H) .: (MH ₂ O) ⁺ 332, (M-2H ₂ O) ⁺ 314.

Example 14 (2E)-(1R, 3R) -5- (11-hydroxy-
7,7,11-Trimethyl-dodeca-2-anylidene)
-As in Preparation Example 12 for cyclohexane-1,3-diol, except that in step d] (3R, 5R)-
Using [2- [3,5-bis- (tert-butyldimethyl-silanyloxy) -cyclohexylidene] -ethyl] -diphenyl-phosphine oxide, (2E)-
(1R, 3R) -5- (11-hydroxy-7,7,1
1-Trimethyl-dodeca-2-anylidene) -cyclohexane-1,3-diol was prepared as a colorless oil.

NMR: (1H, δ, TMS) 0.84 (s, 6H), 1.10-
2.3 (m, 16H + 3OH), 1.22 (s, 6H), 2.47 (dd, 1H), 2.6
3 (dd, 1H), 4.09 (m, 2H), 5.68 (dt, 1H), 5.99 (d,
1H), 6.26 (dd, 1H) .: (MH ₂ O) ⁺ 320, (M-2H ₂ O) ⁺ 302.

Example 15 (1R, 3R) -5-[(2E, 9E) -11-Hydroxy-7,7,11-trimethyl-dodeca-2,9-diene-ylidene] -cyclohexane-1,3-diol Preparation of a] 5,5-dimethyl-oct-7-yn-1-ol 2- (8,8-dibromo-5,5-dimethyl-oct-
5.04 g of 7-enyloxy) -tetrahydro-pyran
(Example 1 / Step i)) (12.66 mmol) was dissolved in 55 ml of anhydrous tetrahydrofuran and treated at -78 ° C with 25.3 ml of n-butyllithium (1.55M, hexane, 3 eq). After 30 minutes, the reaction mixture was poured into crushed ice / NH ₄ Cl, extracted twice with ether, washed with brine, dried over sodium sulfate and the solvent was evaporated. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 95/5) was carried out to give 2- (5,5-dimethyl-
3.07 g of octo-7-ynyloxy) -tetrahydro-pyran was obtained, which was deprotected as follows.

2.00 g (8.39 mmol) thereof was dissolved in 57 ml of methanol, and pyridinium- (toluene-4-
Sulfonate) 211 mg (0.1 eq) and kept at room temperature overnight. Then the reaction mixture is crushed on ice / Na ₂ C.
Poured into O ₃ , extracted twice with ether, washed with water, dried over sodium sulphate and evaporated to dryness. Flash chromatography (SiO ₂ , pentane / methyl acetate = 75/25) gave 1.27 g of the title compound as a colorless oil (GC 99% purity).

NMR: (1H, δ, TMS) 0.96 (s, 6H), 1.30-
1.6 (m, 6H + OH), 1.98 (t, 1H), 2.07 (d, 2H), 3.67
(t, 2H) .: (MC ₃ H ₃ ) ⁺ 115.

B] 5,5,9-Trimethyl-dec-7-
In-l, 9-diol anhydrous tetrahydrofuran 16 ml and 1,5-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (DMPU) in 6.6 ml 5,5-dimethyl-oct-7. -In-1-all 1.27g (8.213mmo
solution of n-butyllithium (1.
55M, hexane, 3 eq.) 15.93 ml was added. After reaching the internal temperature of -20 degrees, at -78 degrees again,
2.42 ml of acetone dissolved in 5 ml of tetrahydrofuran
(4 eq) was added dropwise and the mixture was kept at -78 degrees for 10 minutes. Warmed to ambient temperature, poured into crushed ice / NH ₄ Cl solution, extracted twice with ether, washed with brine, dried over sodium sulphate and solvent evaporated to leave a crude product which was flash chromatographed. Graphography (Si
O _2, hexanes / ethyl acetate = 7 / 3-1 / 1), the starting material 0.75g and heading compound 7
67 mg was obtained as a colorless oil.

NMR: (1H, δ, TMS) 0.94 (s, 6H), 1.30-0
-1.7 (m, 6H + 2OH), 1.51 (s, 6H), 2.06 (s, 2H), 3.68
(t, 2H) .: (M-CH ₃ ) ⁺ 197.

C] (E) -9-hydroxy-5,5,9
Trimethyl-dec-7-enal LiAlH ₄ 433 mg (5 equivalents) was suspended in anhydrous tetrahydrofuran 40 ml and cooled to 0 °. After adding 614 mg (5 equivalents) of sodium methylate, 5, 5, 9
-Trimethyl-dec-7-yne-1,9-diol 48
A solution of 5 mg (2.284 mmol) in 27 ml of tetrahydrofuran was added. The mixture was heated at reflux for 2.5 hours, then at 0 ° C, 3.6 ml of water and 2N NaO.
Carefully quench with 3.6 ml H. Next, 62 ml of ether
Was added and the mixture was vigorously stirred for 20 minutes to complete hydrolysis of the Al salt. Careful drying over magnesium sulfate and evaporation of the solvent left 481 mg of (E) -5,5,9-trimethyl-dec-7-ene-1,9-diol, which was further treated as follows. .

This was oxidized at room temperature over 3.20 g (3.8 equiv.) Pyridinium-dichromate in 71 ml CH ₂ Cl ₂ by stirring overnight. Filter through a pad of silica gel, remove the solvent and flash chromatography (SiO ₂ , hexane / ethyl acetate = 8).
/ 2) was carried out to obtain 233 mg of the captioned compound as a colorless oily substance.

NMR: (1H, δ, TMS) 0.86 (s, 6H), 1.20
(m, 2H), 1.32 (s, 6H), 1.5-1.7 (m, 2H + OH), 1.93 (m,
2H), 2.41 (td, 2H), 5.61 (m, 2H), 9.76 (t, 1H) .:
^{_{(M-CH 3) + 197}} , (MH 2 O) + 194.

D] (E) -5,5,9-trimethyl-9
-Trimethylsilanyloxy-dec-7-enal (E) -9-hydroxy-5,5,9-trimethyl-dec-7-enal 230 mg (1.083 mmol) in CH ₂
Dissolved in 13.5 ml of Cl ₂ and 1- (trimethylsilyl)
Treated with 1.11 ml (7 equivalents) of imidazole. After 20 hours at room temperature, the mixture was poured into crushed ice, extracted twice with ether, washed with brine, dried over sodium sulfate,
Evaporated to dryness. Flash chromatography (SiO ₂ , hexane / ethyl acetate = 95/5) gave 281 mg of the title compound as a colorless oil.

NMR: (1H, δ, TMS) 0.10 (s, 9H), 0.86
(s, 6H), 1.20 (m, 2H), 1.30 (s, 6H), 1.5-1.7 (m, 2
H), 1.91 (d, 2H), 2.41 (td, 2H), 5.54 (m. 2H), 9.76
(t, 1H). :( M) ⁺ 284, (M-CH ₃ ) ⁺ 269.

E] (1R, 3R) -5-[(2E, 9
E) -11-Hydroxy-7,7,11-trimethyl-
Dodeca-2,9-diene-ylidene] -cyclohexane-1,3-diol Carefully dried (3R, 5R)-[2- [3,5-
0.712 g (2.5 equivalents) of bis- (tert-butyldimethyl-silanyloxy) -cyclohexylidene] -ethyl] -diphenyl-phosphine oxide was dissolved in 8 ml of anhydrous tetrahydrofuran and n-butyllithium (-78 ° C) was obtained. 1.55M, hexane) 0.920 ml. After 10 minutes, 0.142 g of (E) -5,5,9-trimethyl-9-trimethylsilanyloxy-dec-7-enal dissolved in 2 ml of anhydrous tetrahydrofuran was added dropwise to the deep red solution. After the mixture was maintained for 1 hour at -78 ° and quenched with solution _of NH ₄ Cl. Extraction twice with ether, washing with brine, drying over sodium sulphate and evaporation of the solvent left a crude product which was subjected to short flash chromatography (SiO ₂ , hexane / ethyl acetate = 7/3). Purification yielded 0.324 g of diastereoisomeric β-hydroxy-phosphine oxide, which was treated as follows.

This intermediate was treated with anhydrous tetrahydrofuran 3.
Dissolved in 5 ml and treated at 0 ° with approximately 4 equivalents of NaH (50% in mineral oil). Slowly raise the temperature to room temperature,
Stirring was continued until thin layer chromatography showed no starting material present (1 hour). After quenching with crushed ice / NH ₄ Cl, the product was extracted with ether, washed with brine, dried over sodium sulfate and the solvent was removed.
Flash chromatography (SiO ₂ , hexane /
Ethyl acetate = 98/2) gave 151 mg of triene as a colorless oil, which was deprotected as follows. _{MS: (M-CH 3)} + 621

1.15 g of tetrabutylammonium fluoride trihydrate in 3.6 ml of tetrahydrofuran
(3.64 mmol) of 3Å molecular sieve 1.56 g
It was carefully dried by stirring through an oven at room temperature for 1.5 hours. This solution was then added to the intermediate prepared above (0.232 mmol) and maintained at 35-40 degrees for 2 hours. The reaction mixture was then poured onto crushed ice, extracted twice with ethyl acetate, washed with brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO ₂ , ethyl acetate; SiO ₂ , hexane / isopropanol = 8/2) for two consecutive times gave 79 mg of the title compound as a colorless oil. Usually the product is contaminated with a small amount of 2Z isomer, which can be removed by HPLC.

NMR: (1H, δ, TMS) 0.84 (s, 6H), 1.10-
2.3 (m, 12H + 3OH), 1.31 (s, 6H), 2.48 (dd, 1H), 2.6
3 (dd, 1H), 4.09 (m, 2H), 5.60 (m, 2H), 5.67 (dt,
1H), 5.99 (d, 1H), 6.27 (dd, 1H) .: (MH ₂ O) ⁺ 318,
(M-2H ₂ O) ⁺ 300. (cm ^-1 ): 3359, 2931, 2842, 1625, 146
8, 1364, 1051, 974.

Example 16 (Z)-(S) -3-[(2E, 9E) -11-hydroxy-7,7,11-trimethyl-dodeca-2,9-diene-ylidene] -4-methylene-cyclohexane -1
-As in Preparation Example 15 for ol, except that in step e], (Z)-(5S)-
[2- [5- (tert-butyldimethyl-silanyloxy) -2-methylene-cyclohexylidene] -ethyl]
Using diphenyl-phosphine oxide (Z)
-(S) -3-[(2E, 9E) -11-hydroxy-
7,7,11-Trimethyl-dodeca-2,9-diene-
Ylidene] -4-methylene-cyclohexan-1-ol was prepared as a colorless oil.

NMR: (1H, δ, TMS) 0.83 (s, 6H), 1.10-
2.5 (m, 13H + 2OH), 1.31 (s, 6H), 2.53 (dd, 1H), 3.9
1 (m, 1H), 4.83 (br s, 1H), 5.05 (br s, 1H), 5.60
(m, 2H), 5.67 (dt, 1H), 5.88 (d, 1H), 6.40 (dd, 1
H) .: (M) ⁺ 332, (MH ₂ O) ⁺ 314. (cm ^-1 ): 3353, 2933, 28
42, 1635, 1440, 1364, 1052.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 43/00 111 A61P 43/00 111 (72) Inventor Mohr, Peter Switzerland, Zeher-4054 Basel, Benkenstrasse 26 ( 72) Inventor Müller, Marc France, F-68300 Saint-Louis, Ryu Adalbert de Barenfels 3 (72) Inventor Pilson, Wolfgang Germany, Day 79576 Weil am Rhein, Am Helen Rhein 4 (56) References International Publication 95/19963 (WO, A1) International Publication 95/01960 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) CA (STN) REGISTRY (STN)

Claims (15)

(57) [Claims] 1. Formula I (Wherein X is C = CH ₂ or CH ₂ , Y and Z are independently of each other hydrogen, fluorine or hydroxy, and A is -C≡C-, -CH = CH- or -CH ₂ -C
H ₂ - a and, R ¹ and R ² are, independently of one another, alkyl or perfluoroalkyl, R ³ is lower alkyl) compounds. 2. The compound of claim 1, wherein at least one of Y and Z is hydroxy. 3. The compound according to claim 1, wherein Y and Z are hydroxy. 4. The compound according to any one of claims 1 to 3, wherein A is -C = C-. 5. (1R, 3R) -5-[(2E, 9Z)
-12,12,12-Trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene) -cyclohexane-1,3
-Diol, (Z)-(1R, 3S) -4-methylene-5-[(2
E, 9Z) -12,12,12-trifluoro-11-
Hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene] -cyclohexane-1,3-diol, (Z)-(1R, 3S) -5-((2E, 9E)- 1
2,12,12-Trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-
2,9-dienylidene) -4-methylene-cyclohexane-1,3-diol, (1R, 3R) -5-[(2E, 9E) -12,12,
12-trifluoro-11-trifluoromethyl-11
-Hydroxy-7,7-dimethyl-dodeca-2,9-dienylidene] -cyclohexane-1,3-diol, (1R, 3R) -5-[(2E, 9E) -11-hydroxy-7,7,11 -Trimethyl-dodeca-2,9-diene-ylidene] -cyclohexane-1,3-diol, or (Z)-(S) -3-[(2E, 9E) -11-hydroxy-7,7,11. -Trimethyl-dodeca-2,9-diene-ylidene] -4-methylene-cyclohexane-1
-The compound of claim 4, which is an all. 6. The method according to claim 1, wherein A is —CH ₂ CH ₂ —.
4. The compound according to any one of 3 above. 7. (1R, 3R) -5-[(2E) -1
2,12,12-trifluoro-11-hydroxy-
7,7-Dimethyl-11-trifluoromethyl-dodeca-2-enylidene) -cyclohexane-1,3-diol, (Z)-(1R, 3S) -5-[(2E) -12,1
2,12-trifluoro-11-hydroxy-7,7-
Dimethyl-11-trifluoromethyl-dodeca-2-anylidene] -4-methylene-cyclohexane-1,3-
Diol, (Z)-(1S) -3-[(2E) -11-hydroxy-7,7,11-trimethyl-dodeca-2-en-ylidene] -4-methylene-cyclohexan-1-ol, (Z )-(1R, 3S) -5-[(E) -11-Hydroxy-7,7,11-trimethyl-dodeca-2-enylidene] -4-methylene-cyclohexane-1,3-diol, or (2E )-(1R, 3R) -5- (11-hydroxy-
7,7,11-Trimethyl-dodeca-2-anylidene)
-Cyclohexane-1,3-diol.
The described compound. 8. The compound according to claim 1, wherein A is —C≡C—. 9. (E)-(1R, 3R) -5- [11-
Hydroxy-7,7-dimethyl-11,11-bis-trifluoromethyl-dodeca-2-ene-9-ynylidene] -cyclohexane-1,3-diol, (Z)-(1R, 3S) -4-methylene -5-[(E)
-11-Hydroxy-7,7-dimethyl-11,11-
Bis-trifluoromethyl-dodeca-2-ene-9-ynylidene] -cyclohexane-1,3-diol, (Z)-(S) -4-methylene-3-[(E) -11-
Hydroxy-7,7-dimethyl-11,11-bis-trifluoromethyl-dodeca-2-en-9-ynylidene] -cyclohexan-1-ol, (10E, 12Z)-(S) -12- (5- Hydroxy-2-methylene-cyclohexylidene) -6,6-dimethyl-2-methyl-dodeca-10-en-3-yne-2
-Ol or (10E)-(3R, 5R) -12- (3,5-dihydroxy-cyclohexylidene) -6,6-dimethyl-2
9. A compound according to claim 8 which is -methyl-dodeca-10-en-3-yn-2-ol. 10. Formula II: (Wherein R ¹ , R ² , R ³ and X are as defined in claim 1, Y ′ and Z ′ are protected hydroxy groups, and R ⁴ is a hydroxy protecting group. ) Compound. 11. For treating or preventing hyperproliferative skin diseases, which comprises a compound of formula I as claimed in any one of claims 1 to 9 as active ingredient and a pharmaceutically acceptable carrier, or A pharmaceutical composition for reversing symptoms associated with photoinjury. 12. The pharmaceutical composition according to claim 11, wherein the hyperproliferative skin disease is psoriasis, basal cell carcinoma, keratinization disorder or keratosis. 13. A compound of formula II in the presence of tetrabutylammonium fluoride in an inert solvent. (Wherein R ¹ , R ² , R ³ and X are as defined in claim 1, Y ′ and Z ′ are protected hydroxy groups, and R ⁴ is a hydroxy protecting group. A process for the preparation of a compound of formula I according to claim 1, comprising cleaving the protecting groups Y ', Z'and R ⁴ contained in the compound)). 14. A method for producing a medicament for treating or preventing a hyperproliferative skin disease, or for reversing a symptom associated with photoinjury. Use of the compound according to item 1. 15. Use according to claim 14, wherein the hyperproliferative skin disease is psoriasis, basal cell carcinoma, keratinization disorders or keratosis.